Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users

Abstract

This study aimed to analyze associations between genetic variants and the occurrence of clinical outcomes in dabigatran, apixaban, and rivaroxaban users. This was a retrospective real-world study linking genotype data of three Finnish biobanks with national register data on drug dispensations and healthcare encounters. We investigated several single-nucleotide variants (SNVs) in the ABCG2, ABCB1, CES1, and CYP3A5 genes potentially associated with bleeding or thromboembolic events in direct oral anticoagulant (DOAC) users based on earlier research. We used Cox regression models to compare the incidence of clinical outcomes between carriers and noncarriers of the SNVs or haplotypes. In total, 1,806 patients on apixaban, dabigatran, or rivaroxaban were studied. The ABCB1 c.3435C>T (p.Ile1145=, rs1045642) SNV (hazard ratio (HR) 0.42, 95% confidence interval (CI), 0.18-0.98, P = 0.044) and 1236T-2677T-3435T (rs1128503-rs2032582-rs1045642) haplotype (HR 0.44, 95% CI, 0.20-0.95, P = 0.036) were associated with a reduced risk for thromboembolic outcomes, and the 1236C-2677G-3435C (HR 2.55, 95% CI, 1.03-6.36, P = 0.044) and 1236T-2677G-3435C (HR 5.88, 95% CI, 2.35-14.72, P < 0.001) haplotypes with an increased risk for thromboembolic outcomes in rivaroxaban users. The ABCB1 c.2482-2236G>A (rs4148738) SNV associated with a lower risk for bleeding events (HR 0.37, 95% CI, 0.16-0.89, P = 0.025) in apixaban users. ABCB1 variants are potential factors affecting thromboembolic events in rivaroxaban users and bleeding events in apixaban users. Studies with larger numbers of patients are warranted for comprehensive assessment of the pharmacogenetic associations of DOACs and their relevance for clinical practice.Direct oral anticoagulants (DOACs) are increasingly used in the context of various clinical conditions and procedures, including atrial fibrillation (ischemic stroke prevention), deep vein thrombosis, and pulmonary embolism. DOACs have favorable pharmacodynamic and pharmacokinetic properties and do not require continuous therapeutic monitoring except in specific

Non‐synonymous alterations in AKR7A3 and ABCA6 correlate with bleeding in aged patients treated with rivaroxaban

“…Pharmacogenomic studies on rivaroxaban mainly focus on single nucleotide polymorphisms (SNPs) of CYP3A4 / 5 and ABCB1 genes. It has been reported that ABCB1 polymorphisms or haplotypes are correlated with peak concentration of rivaroxaban in a steady‐state, 11 and have been associated with rivaroxaban‐induced thrombotic events 12 . However, genetic basis of rivaroxaban‐induced bleeding events has not been fully addressed.…”

Direct Oral Anticoagulants (DOAC): Are We Ready for a Pharmacogenetic Approach?

“…In conclusion, this study suggests that the pharmacogenetic approach to DOACs is a relatively new field of research and that all observations made so far need further consideration and the execution of additional and larger replication studies. In this regard, a recent retrospective study performed on 1806 patients treated with dabigatran, rivaroxaban, or apixaban has identified and confirmed a close correlation between ABCB1 single nucleotide variants and haplotypes with clinical outcomes in rivaroxaban and apixaban users [13]. Similarly, other recent studies have confirmed the correlation between ABCB1 and CES1 SNPs and plasma levels of dabigatran in Chinese patient populations [14].…”

The impact of ABCB1 and CES1 polymorphisms on the safety of dabigatran in patients with non-valvular atrial fibrillation

“…ABCB1 variants are potential factors affecting thromboembolic events in dabigatran users and bleeding events 18 . Earlier studies have found associations between genetic variability and plasma levels of direct oral anticoagulants 19,20 . ABCB1 SNP 1045642 is associated with a reduced risk for thromboembolic outcomes, while rs4148738 is associated with a lower risk for bleeding events in apixaban users.…”